Traditionally, vaccines are derived from material completely foreign to the organism being vaccinated. Nevertheless, it is often desirable to immunize an organism with a vaccine based on proteins derived from the organism itself. For example, control of inflammation, prevention of ovulation or other forms of contraception, inhibition of Alzhiemer's disease, and prevention or inhibition of tumor growth are all conditions which benefit from immunization with endogenous or “self” proteins.
Peptide vaccines can be used to treat subjects with diseased or abnormal cells; for example, cells infected with viruses, intracellular bacteria or parasites, and tumor cells. The peptide vaccine can induce a cytotoxic T lymphocyte (CTL) response against the diseased or abnormal cells. Cytotoxic T lymphocytes (CTLs) destroy diseased or abnormal cells by direct cytotoxicity, and by providing specific and nonspecific help to other immunocytes such as macrophages, B cells, and other types of T cells. Peptide vaccines can also induce an antibody response, which is useful in the prophylactic and therapeutic treatment of the disease or condition.
Current peptide vaccine technology involves identification of an endogenous normal protein which is associated with the pathogenesis of a given condition. The normal whole protein is then used as the basis for a vaccine. Alternatively, portions of the endogenous protein which are predicted to bind to MHC class I or II motifs are identified and used to produce the vaccine. See Falk et al., Nature 351:290, 1991. However, peptide vaccines made only from the partial or whole normal protein sequences can be poorly immunogenic against diseased or abnormal cells, and can also induce an immune reaction against those cells of the body which express the normal protein.
Previous attempts to increase the specific immunogenicity of peptide vaccines have focussed on point mutations in endogenous proteins from various types of cancer cells. These point mutations represent a small area of “non-self” within the larger endogenous protein sequence that may be used to elicit an immune response. However, these point mutations are not effectively recognized by the immune system, and peptide vaccines employing such technology have not produced strong immunologic responses.
Peptide vaccines have also been based on the protein products resulting from gene rearrangements (i.e., deletions, chromosomal rearrangements) that are sometimes present in cancer cells. For example, a chromosome 9:22 translocation in chronic myelogenous leukemia cells produces the BCR/Abl fusion protein. This protein contains an area of “non-self” at the BCR/Abl fusion junction, and has elicited some immunologic response in human patients. However, such gene rearrangements are rare, and chromosomal translocations are only known to occur in cancer. Thus, the usefulness of vaccines produced from protein products derived from chromosomal rearrangements is limited.
Thus, it is desirable to identify endogenous proteins which are specific to certain tissues in a given disease state, and which also contain immunologic areas of “non-self” that produce a strong immune response, such as a CTL or antibody response. Ideally, such altered endogenous proteins would be commonly occurring and induce little or no cross-reactivity to the corresponding normal protein.
Primary RNA transcripts from certain genes can undergo alternative splicing to produce messenger RNA (mRNA) which differs from the majority of the mRNA produced by the gene. These alternatively spliced mRNAs are translated into alternative splice form proteins that contain different amino acid sequences than the corresponding protein produced by normally spliced mRNA. Alternative splice form proteins are often expressed in a tissue-specific manner under certain physiologic or disease states. Consequently, these alternative splice forms are present in a limited number of cells in a subject suffering from a given disease or condition. For example, it is known that many types of cancer cells produce alternative splice forms which are not found in normal cells from the same subject. Other disease states in which alternative splice forms are specifically produced include diabetes, Alzhiemer's disease and systemic lupus erythematosus (SLE). These alternative splice forms have not heretofore been recognized as a source for vaccines directed against cells from diseased or abnormal tissue which produce the alternative splice form.